Project Summary About 74% of schizophrenia patients discontinue use within 18 months of therapy due to either poor tolerability of incomplete efficacy. This underscores the need for novel and more effective therapeutic targets for schizophrenia treatment. Recent clinical studies suggested that the metabotropic glutamate 2/3 receptor (mGlu2/3) agonist LY2140023 had antipsychotic properties, providing a new alternative for the treatment of schizophrenia. Unfortunately, follow-up studies with LY2140023 showed either inconclusive results, or clinical outcomes that were not different from placebo. Our published data demonstrated that chronic treatment with atypical antipsychotics, such as with clozapine or risperidone, but not with typical antipsychotics, such as haloperidol, induces repressive histone modifications at the mGlu2 (Grm2) promoter in mouse and human frontal cortex. Remarkably, the translational significance of our preclinical findings has been validated by a recent post-hoc analysis: patients previously treated with typical antipsychotics responded to LY2140023, whereas the effects of LY2140023 in patients previously exposed to atypical antipsychotics did not differ from placebo. Our published and preliminary data also suggest that these repressive epigenetic modifications occurred through a signaling mechanism that requires a serotonin 5-HT2A receptor (5HT2A)-dependent enhancement of NF-?B transcriptional function via I?B?, which is followed by NF-?B-dependent up-regulation and increased binding of histone deacetylase 2 (HDAC2) to the mGlu2 promoter. We have focused our investigation on the potential role of HDAC2 as the basic molecular mechanism underlying down-regulation of mGlu2 expression after chronic antipsychotic drug treatment. Our results are expected to provide a route to the identification of new and more effective epigenetic drugs to improve the currently limited response to treatment with glutamate antipsychotics.